Lupus erythematosus (LE describes a heterogeneous group of autoimmune skin diseases, some of which are associated with systemic (SLE) as well as skin disease. The various LE skin lesions occur in diverse subpopulations with differing propensities for systemic disease, different HLA associations, autoantibody (autoAb) associations, and with differing chronicity and prognosis. They also differ in their histopathology and quite likely in their pathogenesis. In this regard, in spite of significant descriptive study and multiple classification schemes, little is known about the pathogenesis of these lesions. One of the problems in deciphiring the pathogenesis of this or any spontaneous autoiminune syndrome is the complex and interrelated set of events that ultimately lead to the pathologic picture. We plan to exploit a murine model of lupus skin lesions. the MRL mouse. in order to better understand the pathogenesis of these lesions. These mice, in addition to developing a syndrome serologically and clinically similar to human SLE, spontaneously develop skin lesions that resemble discoid LE (DLE). However, with the exception of Furukawa and colleagues, skin disease in these strains has been little studied. Accordingly, to better understand both the induction of self-reactivity as well as end organ damage in the MRL/pr lupus model, along with Dr. Joe Craft, we have created or bred MRL mice which are genetically deficient in either: B cells, alphabeta T cells. CD40L, gammadelta T cells, or beta2-microglobulin (beta2m). Among these mice, we found that B-deficient mice completely lacked the characteristic infiltrative DLE-like lesions. In Aim l, we will use several approaches of partial reconstitution to determine whether this is due to a role for autoAbs, B cells per se, or both. Perhaps most surprisingly, we found that beta2m -/- MRL/lpr/lpr mice had a markedly accelerated and severe skin lesion, while kidney disease in these same mice was markedly reduced. This dissociation of skin and renal immunopathology was unique among the knockouts and treated mice studied by us and others. Beta2m -/- mice may have a number of deficiencies, including the lack of CD8+ T cells and CD1 expression. Therefore, in Aim 2 we will distinguish a number of possible mechanisms by which the lack of beta2m could promote skin disease. It is hoped that by these initial studies, substantial insight will be gained into the mechanisms by which B cells promote DLE-like disease (and thus into the genesis of DLE itself) and why the lack of beta2m promotes disease, but only in the skin. In addition, reconstitutions will allow observation and delineation of the primary events in pathogenesis.